Targeting aspartate beta-hydroxylase suppresses tumor malignancy and metastasis

Abstract

Disclosed are methods of treating a cell proliferative disease (e.g., cancer) by administering compounds which inhibit the activity of beta-hydroxylase (e.g., ASPH). Further disclosed are methods suppressing metastasis in a cancer cell by contacting the cancer cell with the compounds.

What is claimed is: 
     
         1 . A method of treating a cell proliferative disease comprising administering a therapeutically effective amount of an asparatyl (asparaginyl) beta-hydroxylase (ASPH) inhibitor to a subject in need thereof. 
     
     
         2 . The method of  claim 1 , wherein the ASPH inhibitor has a structure of 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein the cell proliferative disease comprises a cancer. 
     
     
         4 . The method of  claim 3 , wherein cells of the cancer express greater level of ASPH than normal cells. 
     
     
         5 . The method of  claim 4 , wherein the ASPH inhibitor suppresses metastasis in the cancer cells. 
     
     
         6 . The method of  claim 4 , wherein the cancer comprises liver cancer, pancreatic cancer, lung cancer, colon cancer, breast cancer, gastric cancer, sarcoma, renal cancer, prostate cancer, brain cancer, or leukemia. 
     
     
         7 . The method of  claim 4 , wherein the liver cancer comprises hepatocellular cancer, or cholangiocarcinoma. 
     
     
         8 . The method of  claim 4 , wherein the lung cancer comprises small cell lung cancer, non-small cell lung cancer, or metastatic lung cancer. 
     
     
         9 . The method of  claim 4 , wherein the brain cancer comprises gliomas, meningioma, astrocytomas, or glioblastoma. 
     
     
         10 . The method of  claim 4 , wherein the breast cancer comprises ductal carcinoma, triple negative breast cancer, inflammatory breast cancer, metastatic breast cancer, medullary carcinoma, tubular carcinoma, or mucinous carcinoma. 
     
     
         11 . The method of  claim 4 , wherein the gastric cancer comprises stomach cancer, gastric lymphoma, gastrointestinal stromal tumor (GIST), or neuroendocrine (carcinoid) tumor. 
     
     
         12 . The method of  claim 4 , wherein the sarcoma comprises soft tissue sarcoma and osteosarcoma. 
     
     
         13 . The method of  claim 4 , wherein the leukemia comprises myeloid leukemia and lymphoid leukemia. 
     
     
         14 . The method of  claim 1 , wherein the ASPH inhibitor has a structure of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein 
 Ar 1  is substituted or unsubstituted C 6 -C 20  aryl or 5 to 20-membered heteroaryl; 
 X is —C(O)—, —C(S)—, or —S(O) 2 —; 
 W 1  is a single bond, —O—, —CR 50 R 51 —, or —NR 52 — when X is —C(O)—, or W 1  is a single bond, —CR 50 R 51 —, or —NR 52 — when X is —SO 2 —; and 
 each of R 50 , R 51 , R 52 , and R 53  independently is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted C 6 -C 20  aryl, substituted or unsubstituted C 7 -C 26  arylalkyl, substituted or unsubstituted 5 to 20-membered heteroaryl, and substituted or unsubstituted 6-26 membered heteroarylalkyl. 
 
     
     
         15 . The method of  claim 14 , wherein R 53  is unsubstituted C 1 -C 6  alkyl or phenyl, or C 1 -C 6  alkyl or phenyl substituted with one or more substituents selected from halogen, —OH, —CN, —COOCH 3 , and amino. 
     
     
         16 . The method of  claim 14 , wherein the ASPH inhibitor has a structure of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein 
 each of Ar 1  and Ar 2  independently is unsubstituted C 6 -C 14  aryl, unsubstituted 5 to 14-membered heteroaryl, or C 6 -C 14  aryl or 5 to 14-membered heteroaryl each substituted with one or more substituents selected from the group consisting of halogen, —CN, —NO 2 , —NO, —N 3 , —OR a , —NR a R22 b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR b C(O)R a , —S(O) b R a , —S(O) b NR a R b , or —R S1 , in which R S1  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 5- or 6-membered heteroaryl, or 4 to 12-membered heterocycloalkyl, b is 0, 1, or 2, each of R a  and R b , independently is H or R S2 , and R S2  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; and each of R S1  and R S2 , is optionally substituted with one or more substituents selected from the group consisting of halo, OH, oxo, C(O)OH, C(O)O—C 1 -C 6  alkyl, CN, C 1 -C 6  alkyl, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
 
     
     
         17 . The method of  claim 14 , wherein X is C(O) and W 1  is —O—. 
     
     
         18 . The method of  claim 14 , wherein X is —S(O) 2 — and W 1  is —CR 50 R 51 — or a single bond. 
     
     
         19 . The method of  claim 14 , wherein each of R 5 , R 51 ,and R 52  independently is H, unsubstituted C 1 -C 6  alkyl, or C 1 -C 6  alkyl substituted with one or more substituents selected from halo, OH, CN, and amino. 
     
     
         20 . The method of  claim 16 , wherein each of Ar 1  and Ar 2  independently is selected from phenyl, 1-naphthyl, 2-naphthyl, 2-furanyl, 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-carboxymethylphenyl, 3-carboxymethylphenyl, 4-carboxymethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-chloro-6-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 4-chloro-2-fluorophenyl, and 5-chloro-2-fluorophenyl. 
     
     
         21 . The method of  claim 14 , wherein the ASPH inhibitor is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         22 . The method of  claim 1 , wherein the ASPH inhibitor is administered intravenously, orally, subcutaneously, intranasally, intraspinally, intrathecally, intramuscularly, intrabronchially, intrarectally, intraocularly, intravaginally, or by surgical implantation. 
     
     
         23 . A method of suppressing metastasis in a cancer cell contacting the cancer cell with a therapeutically effective amount of an asparatyl (asparaginyl) beta-hydroxylase (ASPH) inhibitor. 
     
     
         24 . The method of  claim 23 , wherein the ASPH inhibitor has a structure of 
       
         
           
           
               
               
           
         
       
     
     
         25 . The method of  claim 23 , wherein the cancel cell expresses greater level of ASPH than a normal cell. 
     
     
         26 . The method of  claim 25 , wherein the cancer cell is from liver cancer, pancreatic cancer, lung cancer, colon cancer, breast cancer, gastric cancer, sarcoma, renal cancer, prostate cancer, brain cancer, or leukemia. 
     
     
         27 . The method of  claim 26 , wherein the liver cancer comprises hepatocellular cancer, or cholangiocarcinoma. 
     
     
         28 . The method of  claim 26 , wherein the lung cancer comprises small cell lung cancer, non-small cell lung cancer, or metastatic lung cancer. 
     
     
         29 . The method of  claim 26 , wherein the brain cancer comprises gliomas, meningioma, astrocytomas, or glioblastoma. 
     
     
         30 . The method of  claim 26 , wherein the breast cancer comprises ductal carcinoma, triple negative breast cancer, inflammatory breast cancer, metastatic breast cancer, medullary carcinoma, tubular carcinoma, or mucinous carcinoma. 
     
     
         31 . The method of  claim 26 , wherein the gastric cancer comprises stomach cancer, gastric lymphoma, gastrointestinal stromal tumor (GIST), or neuroendocrine (carcinoid) tumor. 
     
     
         32 . The method of  claim 26 , wherein the sarcoma comprises soft tissue sarcoma and osteosarcoma. 
     
     
         33 . The method of  claim 26 , wherein the leukemia comprises myeloid leukemia or lymphoid leukemia. 
     
     
         34 . The method of  claim 23 , wherein the ASPH inhibitor has a structure of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein 
 Ar 1  is substituted or unsubstituted C 6 -C 20  aryl or 5 to 20-membered heteroaryl; 
 X is —C(O)—, —C(S)—, or —S(O) 2 —; 
 W 1  is a single bond, —O—, —CR 50 R 51 —, or —NR 52 — when X is —C(O)—, or W 1  is a single bond, —CR 50 R 51 —, or —NR 52 — when X is —SO 2 —; and 
 each of R 50 , R 51 , R 52 , and R 53  independently is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted C 6 -C 20  aryl, substituted or unsubstituted C 7 -C 26  arylalkyl, substituted or unsubstituted 5 to 20-membered heteroaryl, and substituted or unsubstituted 6-26 membered heteroarylalkyl. 
 
     
     
         35 . The method of  claim 34 , wherein R 53  is unsubstituted C 1 -C 6  alkyl or phenyl, or C 1 -C 6  alkyl or phenyl substituted with one or more substituents selected from halogen, —OH, —CN, —COOCH 3 , and amino. 
     
     
         36 . The method of  claim 34 , wherein the ASPH inhibitor has a structure of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein 
 each of Ar 1  and Ar 2  independently is unsubstituted C 6 -C 14  aryl, unsubstituted 5 to 14-membered heteroaryl, or C 6 -C 14  aryl or 5 to 14-membered heteroaryl each substituted with one or more substituents selected from the group consisting of halogen, —CN, —NO 2 , —NO, —N 3 , —OR a , —NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR b C(O)R a , —S(O) b R a , —S(O) b NR a R b , or —R S1 , in which R S1  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 5- or 6-membered heteroaryl, or 4 to 12-membered heterocycloalkyl, b is 0, 1, or 2, each of R a  and R b , independently is H or R S2 , and R S2  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; and each of R S1  and R S2 , is optionally substituted with one or more substituents selected from the group consisting of halo, OH, oxo, C(O)OH, C(O)O—C 1 -C 6  alkyl, CN, C 1 -C 6  alkyl, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 1 o aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
 
     
     
         37 . The method of  claim 34 , wherein X is C(O) and W 1  is —O—. 
     
     
         38 . The method of  claim 34 , wherein X is —S(O) 2 — and W 1  is —CR 50 R 51 — or a single bond. 
     
     
         39 . The method of  claim 34 , wherein each of R 5 , R 51 ,and R 52  independently is H, unsubstituted C 1 -C 6  alkyl, or C 1 -C 6  alkyl substituted with one or more substituents selected from halo, OH, CN, and amino. 
     
     
         40 . The method of  claim 36 , wherein each of Ar 1  and Ar 2  independently is selected from phenyl, 1-naphthyl, 2-naphthyl, 2-furanyl, 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-carboxymethylphenyl, 3-carboxymethylphenyl, 4-carboxymethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-chloro-6-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 4-chloro-2-fluorophenyl, and 5-chloro-2-fluorophenyl. 
     
     
         41 . The method of  claim 34 , wherein the ASPH inhibitor is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         42 . The method of  claim 23 , wherein the ASPH inhibitor is administered intravenously, orally, subcutaneously, intranasally, intraspinally, intrathecally, intramuscularly, intrabronchially, intrarectally, intraocularly, intravaginally, or by surgical implantation.